13-48411503-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001162498.3(LPAR6):c.921G>T(p.Trp307Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,612,538 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (8 hom., cov: 32)
  • Exomes 𝑓: 0.012 (109 hom.)
• Consequence: LPAR6 NM_001162498.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.29

Genes affected

LPAR6 (HGNC:15520): (lysophosphatidic acid receptor 6) The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene aligns with an internal intron of the retinoblastoma susceptibility gene in the reverse orientation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2009]

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00554204).
• BP6: Variant 13-48411503-C-A is Benign according to our data. Variant chr13-48411503-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 774331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00826 (1258/152222) while in subpopulation NFE AF= 0.0125 (847/67988). AF 95% confidence interval is 0.0118. There are 8 homozygotes in gnomad4. There are 624 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPAR6	NM_001162498.3	c.921G>T	p.Trp307Cys	missense_variant	1/1	ENST00000620633.5
RB1	NM_000321.3	c.1695+30060C>A		intron_variant		ENST00000267163.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPAR6	ENST00000620633.5	c.921G>T	p.Trp307Cys	missense_variant	1/1	5	NM_001162498.3	P1
RB1	ENST00000267163.6	c.1695+30060C>A		intron_variant		1	NM_000321.3	P1

Frequencies

GnomAD3 genomes AF: 0.00828 AC: 1259 AN: 152104 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00875 AC: 2179 AN: 249030 Hom.: 15 AF XY: 0.00870 AC XY: 1172 AN XY: 134644

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.000600

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00427

Gnomad FIN exome AF: 0.0205

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0124 AC: 18063 AN: 1460316 Hom.: 109 Cov.: 31 AF XY: 0.0122 AC XY: 8828 AN XY: 726460

Gnomad4 AFR exome AF: 0.00219

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.000767

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00524

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00826 AC: 1258 AN: 152222 Hom.: 8 Cov.: 32 AF XY: 0.00838 AC XY: 624 AN XY: 74430

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00747

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0109 Hom.: 33

Bravo AF: 0.00649

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.00920 AC: 1117

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0114

EpiControl AF: 0.0112

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	LPAR6: BP4, BS1, BS2; RB1: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Retinoblastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Benign	0.87
DEOGEN2	Benign	0.0075	T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.51	N;.;N
REVEL	Benign	0.14
Sift	Benign	0.048	D;.;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.33
MutPred		0.18		Loss of MoRF binding (P = 0.038);Loss of MoRF binding (P = 0.038);Loss of MoRF binding (P = 0.038);
MVP		0.82
MPC		0.18
ClinPred		0.085	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17071686; hg19: chr13-48985639;